In 2001, the world wide number of patients with dementia was approximately 24 million and is expected to increase to 84 million people by the year 2040. Vascular factors appear to be a major component to dementia including those factors involving coagulation. Tissue Factor Pathway Inhibitor (TFPI) is the primary physiological inhibitor of tissue factor, the initiator of clotting after a blood vessel has been damaged, and FXa, a major component of the clotting system that produces a large amount of thrombin resulting in clot formation. TFPI is found in endothelial cells, in platelets or in plasma. In plasa it is either bound to the plasma lipoproteins, predominately LDL, with less anti-coagulant activity or in an active free unbound form. Another anti-coagulant protein, Protein S (PS), directly interacts with TFPI promoting an enhanced inhibition of FXa. Mouse models of either tfpi-/- and pros-/- mice die in utero and have intravascular fibrin clots in the brain. Normal variations in plasma TFPI and PS concentrations are strongly influenced by polymorphisms in their respective structural genes. Several TFPI polymorphisms and PS polymorphisms have been associated with deep vein thrombosis, however, it is not known if polymorphisms of these two interactive proteins cause micro- brain infarcts and dementia. Preliminary data demonstrate that mouse models lacking either endothelial cell or platelet TFPI produce intravascular fibrin micro-clots preferentially in the brain suggesting a critical amount of TFPI and /or PS are necessary to prevent abnormal clotting in the brain. We have techniques available within our laboratory to translate the data from mouse models to the disease of human dementia using DNA and plasma specimens from the NHLBI BioLINCC Honolulu Heart Project consisting of a homogenous population of Japanese and Japanese-Americans residing in Honolulu. Of interest are the 404 individuals with and without dementia who later came to autopsy in which brain pathology was characterized.
In Aim1 we will sequence the exons and 5'promoter region of the TFPI gene in all individuals to identify any polymorphisms and correlate the polymorphisms with TFPI plasma concentrations and anti-FXa activity.
In Aim2 we will identify individuals with the PS 196K>E polymorphism which is found uniquely in the Japanese population and correlate this polymorphism with the PS plasma concentration and anti-thrombotic activity.
In Aim3 we will correlate the TFPI plasma concentrations and activity with lipoprotein levels and ApoE genotype of the cohort which have been previously determined. At the conclusion of these studies, we will have identified TFPI polymorphisms associated with dementia and determined the TFPI plasma concentrations and activity with the polymorphisms, determined the relationship of the 196K>E PS polymorphism to dementia and correlated the associated plasma concentration and activity of PS with dementia, and determined the relationship of TFPI to ApoE. Finally, other risk factors of cardiovascular disease found within the BioLINCC database will be used in a linear regression model to determine the significance of TFPI and PS on the pathogenesis of dementia.
Dementia is a devastating disease of increasing importance as the population in the United States ages. It has high human and financial cost. Tissue factor pathway inhibitor (TFPI) and its cofactor, Protein S (PS), prevent development of small blood clots within the blood vessels of mouse brain. This project will investigate how TFPI, PS, and Apolipoprotein E contribute to the development of small blood clots in human brain that may accelerate memory loss. The results will lead to new understanding of the biochemical events that lead to human dementia.
|Ellery, Paul E R; Maroney, Susan A; Martinez, Nicholas D et al. (2014) Translation of human tissue factor pathway inhibitor-* mRNA is controlled by alternative splicing within the 5' untranslated region. Arterioscler Thromb Vasc Biol 34:187-95|
|Wood, Jeremy P; Ellery, Paul E R; Maroney, Susan A et al. (2014) Protein S is a cofactor for platelet and endothelial tissue factor pathway inhibitor-* but not for cell surface-associated tissue factor pathway inhibitor. Arterioscler Thromb Vasc Biol 34:169-76|
|Wood, Jeremy P; Ellery, Paul E R; Maroney, Susan A et al. (2014) Biology of tissue factor pathway inhibitor. Blood 123:2934-43|
|Maroney, Susan A; Hansen, Karen G; Mast, Alan E (2013) Cellular expression and biological activities of alternatively spliced forms of tissue factor pathway inhibitor. Curr Opin Hematol 20:403-9|